1. Field of the Invention
The present invention involves the treatment of dermal disorders, wounds and infections in humans and is more particularly directed toward compositions and methods for the treatment and prophylaxis of dermal wounds, chronic non-healing wounds, burns, disease, and other dermal disorders.
2. Discussion
As human skin lost its hair cover through the centuries, it underwent many adaptive changes which gave it strength and resilience. The outer layer, while remaining thin to allow suppleness, attained remarkable biological ruggedness, protecting the skin from physical and chemical injury and from the invasion of micro-organisms. Human skin is elastic to accommodate size increases and decreases of the body it encases and to accommodate the many subtle movements that characterize the human body.
Continuously exposed to trauma, human skin has inherent mechanisms that enable it to adapt to new situations and to withstand the onslaught of injurious environmental conditions. Skin repairs expertly and with dispatch the perennial minor injuries it suffers and, given an opportunity, repairs major injuries as well. Many injuries to the skin, such as burns or cuts, however, result in healed skin that displays scarring as well as reduced elasticity, tensile strength and other characteristics. The scarred skin is not only less aesthetically appealing, but also less functional.
The surface of the skin is normally never sterile. At birth, or soon after, it becomes populated with germs, which all but the most stringent measures fail to remove. These pathogenic microorganisms are ubiquitous and, as opportunistic parasites, usually become invasive and infectious when the body's normal barriers to infection are compromised. Examples of the compromise of dermal barriers include disruption of the physical integrity of the skin by puncture or other trauma, burns, pressure wounds from bedridden patients, and immune compromised patients, e.g., patients undergoing chemotherapy or radiation therapy. Numerous microbial infections are associated with skin disease and, for illustrative purposes only, a few of these types are presented as follows.
One of the many types of bacterial skin disease is impetigo, a localized infection of the skin superficial layers, which is caused by an infection of Streptococcus bacteria usually in association with Staphylococcus. Dermal fungal mycoses are caused by three genera of closely related fungal dermatophytes which infect superficial keratinized tissues particularly the skin, hair, and nails. These mycelial fungi can infect the skin and cause common diseases such as Tinea pedis (Athletes foot), Tinea corporis (Ringworm), and Tinea capitis (Ringworm of the scalp).
Viruses which are causative agents of localized infections of the skin and mucous membranes are well known. Herpes simplex virus can cause vesicular eruptions of the skin or mucous membranes and papilloma viruses can cause benign skin tumors commonly know as warts. Anaerobic and aerobic bacteria may act independently or synergistically to form infections of the skin and soft tissues usually as a result of trauma or wounds. Gangrene and cellulitis are examples of this type of skin and soft tissue disease resulting from bacterial infection. Additionally, nosocomial infections by antibiotic resistant Staphylococci present a major problem for infection control in modern hospitals, particularly to patients requiring invasive treatments such as surgery.
Certainly it is in man's best interest to heal dermal disorders as quickly as possible, and for the healed skin to have the same characteristics as undamaged skin. In this manner the body's primary barrier to infection is restored, and the healed skin is both aesthetically appealing and functions as well as undamaged skin. Unfortunately, though, man is still hopelessly ignorant about many of the anatomical, physiological, and biochemical properties of skin and about most of its numerous disorders. To date, much of man's effort to facilitate the healing of dermal disorders has focused on prevention of microbial infection. Innumerable compounds have been tested in an attempt to discover an effective antiseptic for treating and preventing microbial infection. Antiseptics are substances that check the growth or action of microorganisms, especially in or on living tissue. At one time, tincture of iodine was among the most widely used antiseptics, but suffered the well-known drawback of being very irritating to the body tissues. Various chlorine compounds have since been found to have strong antiseptic properties with much lower irritating characteristics. Chlorine dioxide (ClO.sub.2) and "stabilized" chlorine dioxide have been found to be especially desirable antiseptics.
Chlorine dioxide is an oxidizing agent which has strong biochemical activity. In industrial applications, chlorine dioxide is generally regarded as superior even to gaseous chlorine in eliminating algae and other organic material in addition to removing odors and tastes. Chlorine dioxide is also considered as effective as chlorine gas, if not more effective, as a bactericide, virucide and sporicide. Biochemically, however, chlorine dioxide functions in many ways other than as a mere germicide, as noted in U.S. Pat. No. 4,855,135. These other functions include: (a) oxidation of double bonds between two carbon atoms; (b) oxidation of unsaturated fatty acids (lipids) via double bonds between two carbon atoms; (c) acceleration of hydrolysis of carboxylic anhydrides; (d) oxidation of aldehydes to the corresponding carboxylic acids; (e) oxidation of alcohols; (f) oxidation of amines; (g) oxidation of phenols, phenolic derivatives and thiophenolic compounds; (h) moderate oxidation of hydroquinones; (i) oxidation of amino acids, proteins and polyamides; (j) oxidation of nitrates and sulphides; and (k) alteration of the CHO and CH.sub.2 OH radicals of carbohydrates to produce carboxylic functions. Thus, chlorine dioxide is a highly reactive, unstable radical and its biochemical reaction is one of strong oxidation.
Concentrated chlorine dioxide in its liquid or gaseous state is highly explosive and poisonous. This danger prohibits the use of chlorine dioxide in a concentrated form by all but the largest and most sophisticated users. Smaller and somewhat less sophisticated users have often produced chlorine dioxide by acidification of chlorite, a chlorine dioxide liberating compound available in both powder and liquid form. Acid generation of chlorine dioxide has been reported in the literature using a wide variety of inorganic and organic acids. Generally, any acid may be used including strong acids such as hydrochloric acid and sulfuric acid and relatively weak acids such as citric and tartaric acid.
A drawback of acid-induced generation of chlorine dioxide, though, is that it does not result in a stable chlorine dioxide generating solution, but instead provides a rapid generation of chlorine dioxide. The result is a relatively short generation of chlorine dioxide, after which the solution has few, if any, disinfecting characteristics. Increasing the concentration of chlorite and acid prolongs the period of chlorine dioxide generation but can lead to toxicity problems as well as generation of more chlorine dioxide than is required.
There have been numerous attempts to control the rate of production of chlorine dioxide, and all have met with limited success. For instance, U.S. Pat. No. Re. 31,779 (a reissue of U.S. Pat. No. 4,084,747) to Alliger discloses a germ-killing composition comprising a water soluble chlorite, such as sodium chlorite, and lactic acid. As disclosed therein, the particular composition possesses improved disinfectant properties, properties not attained by using the same composition but replacing the lactic acid with other acids such as phosphoric acid, acetic acid, sorbic acid, fumaric acid, sulfamic acid, succinic acid, boric acid, tannic acid, and citric acid. The germ-killing composition is produced by contacting an acid material containing at least 15% by weight of lactic acid with sodium chlorite in aqueous media, the amount of lactic acid being sufficient to lower the pH of the aqueous media to less than about 7. The methods disclosed of disinfecting and sanitizing a germ-carrying substrate, such as skin, include either application of the germ-killing composition, or application of the reactants to provide in situ production thereof.
Other patents disclose acid induced generation of chlorine dioxide from a metal chlorite by defining the chlorite concentration in terms of a limiting chlorous acid concentration. For example, U.S. Pat. No. 5,384,134 to Kross et al. discloses a method for treating dermal disorders wherein a first gel, which comprises a metal chlorite, is mixed with a second gel, which comprises a protic acid. The chlorite ion concentration in the form of chlorous acid is limited to no more than about 15% by weight of the total amount of chlorite ion concentration in the composition. The mixture of the two gels purportedly generates chlorine dioxide over an extended time of up to 24 hours.
Others refer to "stabilized" chlorine dioxide as a means of chlorine dioxide generation. The term stabilized chlorine dioxide refers to various compositions in which the chlorine dioxide is believed to be held in solution in the form of a labile complex. The stabilization of chlorine dioxide by the use of perborates was disclosed in U.S. Pat. No. 2,701,781 to de Guevara. According to the de Guevara patent, an antiseptic solution of stabilized chlorine dioxide can be formed from an aqueous solution of chlorine dioxide and an inorganic boron compound with the boron compound and the chlorine dioxide being present in the solution as a labile complex. The chlorine dioxide, fixed in this stable condition, is an essential ingredient of the antiseptic solution. The de Guevara patent discloses that the chlorine dioxide may be introduced into the compositions either by generation in situ or by external generation and subsequent introduction, such as by bubbling into the aqueous solution. Various methods may be employed for the external production of the chlorine dioxide, such as reaction of sulfuric acid with potassium chlorate or the reaction of the chlorate with moist oxalic acid. Alternatively, chlorine dioxide can be generated in situ by reaction of potassium chlorate and sulfuric acid. Note that whether the chlorine dioxide is produced in situ or externally, it is essentially an acid induced liberation of the chlorine dioxide from potassium chlorate.
U.S. Pat. No. 3,271,242 issued to McNicholas et al. also describes methods for preparing aqueous solutions of stabilized chlorine dioxide for use as antiseptic or bleaching agents. The McNicholas et al. reference discloses generating chlorine dioxide in any well-known manner, such as by the method of Example II of the de Guevara patent, and bubbling it into a solution of water containing a peroxy compound. According to the McNicholas et al. reference, in such solutions the chlorine dioxide is said to be retained in the solution as a labile complex when the solution is alkaline, and is released when the solution becomes acid. For antiseptic use, the reference discloses that the pH of the solution preferably is neutral or slightly alkaline. The chlorine dioxide molecule is said to be released from solution when in a slightly acid environment, such as that associated with the presence of bacteria. It is important to note, however, that the peroxy compounds present in the solution are themselves strongly oxidizing and capable of serving as an antiseptic agent. It is also important to note the methods disclosed rely on acid induced generation of chlorine dioxide.
Much less research has been devoted to the development of compositions and processes for the treatment of dermal disorders which function to facilitate the rapid healing of the skin and to achieve healed skin with the same appearance and characteristics as undamaged skin. U.S. Pat. No. 4,317,814 issued to Laso describes stabilized chlorine dioxide preparations for treatment of burns in humans. Aqueous mixtures of perborate stabilized solutions of chlorine oxides, such as chlorine dioxide, in combination with glycerin are described for topical application to burned areas and may also be administered by oral application for treatment of burns. The aqueous solutions of perborate stabilized chlorine oxides are disclosed as being prepared by mixing with water the following: sodium chlorite, sodium hypochlorite, hydrochloric acid, sulfuric acid, an inorganic perborate, and a peroxy compound, such as sodium perborate. Thus, the solutions prepared in accordance with the Laso patent contain chlorine dioxide, hypochlorite and peroxy compounds as strong oxidizing agents and appear to utilize acid activation of the chlorine dioxide. The Laso patent states that the methods disclosed therein resulted in an immediate subsidence of burn related pain in many cases. The patent describes healing as rapid and characterized by an absence of infection and contraction. Burn scars were smooth and resembled normal tissue, thus eliminating the need for plastic surgery in certain cases.
Antibiotic compounds have also been commonly used for the therapeutic treatment of burns, wounds and skin infections. While antibiotics may provide an effective form of treatment, several dangers are often associated with the use of antibiotics in the clinical environment. These dangers may include but are not limited to: (1) changes in the normal flora of the body, with resulting "superinfection" due to overgrowth of antibiotic resistant organisms; (2) direct antibiotic toxicity, particularly with prolonged use which can result in damage to kidneys, liver and neural tissue depending upon the type of antibiotic; (3) development of antibiotic resistant microbial populations which defy further treatment by antibiotics.
While the above efforts have met with some success, there continues to be a need for new compositions useful in facilitating the healing of dermal disorders which would preferably include antiseptic properties and low levels of irritation and toxicity, as well as quicker healing and increased reduction of scarring.